This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the complete virus-specific response, with the ultimate goal of creating an AIDS vaccine that elicits CD8+ T lymphocyte (CD8-TL) responses. Despite many years of effort, it is becoming clear that the full extent of the CD8-TL response against AIDS viruses is not well understood. We have obtained exciting new data that indicate that a vaccine that solely elicits cellular immune responses can control acute phase virus replication of a heterologous challenge. We also recently discovered that CD8-TL responses directed against a cryptic epitope, derived from an alternate reading frame of the Env gene, was potent at restricting virus replication and selecting for viral escape. We have since found that recognition of cryptic epitopes is a common occurrence in SIV-infection. Based on these exciting data, we hypothesize that including cORFs in a vaccine regimen will increase the breadth of the elicited immune response and will enhance viral control upon infection. Here, we propose a series of experiments that will shed light on the role cryptic epitope-specific responses play in controlling AIDS virus-replication. In the R21 phase, we will examine the total extent of cryptic epitope-specific responses by scanning SIV-infected macaques for responses to overlapping peptides spanning all cryptic ORFs in the SIVmac239 genome. PROGRESS: The experiments performed for this R21 are simple in design. We are testing whether SIV-infected macaques make CD8 T cell responses against cryptic epitopes, epitopes derived from translation of portions of the viral genome that 'should'not be translated, or from translation in the wrong, or antisense direction. We have been quite successful in finding these. We have identified more than 10 new translation products in the forward direction that contain CD8 T cell epitopes and recently we have identified five translation products in the antisense direction. PUBLICATION: Maness, N.J., A.D. Walsh, S.M. Piaskowski, J. Furlott, H.L. Kolar, A.T. Bean, N.A. Wilson, and D.I. Watkins. 2010. CD8+ T cell recognition of cryptic epitopes is a ubiquitous feature of AIDS virus infection. J. Virol 84(21): 11569-74. PMID 20739530. PMCID: PMC2953171.